Surrogate Beta Cells

Cells that have been genetically manipulated to act like the beta cells of the pancreas, which sense glucose levels and make and release insulin. It is hoped that surrogate beta cells could some day be used to treat diabetes.

Thanks to recent advances in pancreatic islet transplantation, in which clusters of insulin-producing beta cells are transplanted from donor pancreases to the recipient’s liver, this procedure now has an improved success rate. It has been shown to vastly improve blood glucose control in people with Type 1 diabetes, sometimes freeing them from the need for injected insulin. However, not nearly enough donor pancreases become available each year to provide islet transplants for everyone who could benefit from them. What’s more, current methods of islet transplantation still require the use of powerful immunosuppressive drugs to ward off rejection of the islets (as well as the autoimmune process that, in the case of Type 1 diabetes, causes diabetes in the first place). The need for these drugs makes islet transplantation unsuitable for many people, including children. Islet transplantation can therefore become widely used only if researchers can both come up with new sources of insulin-producing cells and bypass the need for immunosuppression.

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Surrogate beta cells – cells that didn’t start as beta cells but that can be made to mimic what beta cells do – may be the key. However, creating such cells is no easy task. Surrogate beta cells have to make and secrete insulin and do so in a glucose-dependent fashion. That is, they need to increase their insulin secretion when blood glucose levels are high and ease off when blood glucose levels fall, so that blood glucose levels remain in the normal range.

Since a transplant recipient’s own cells would be used to make surrogate beta cells, there might be no need for immunosuppressive medicines. Researchers also hope that the immune system would not recognize the surrogate cells as beta cells and would therefore not launch the type of autoimmune attack that causes Type 1 diabetes.

To make surrogate beta cells, researchers use vectors (such as harmless viruses) to introduce new genetic information into non-beta cells. This approach, called gene therapy, is still considered experimental but holds great promise for treating or curing a number of diseases.

One very promising source of surrogate beta cells is the liver. The liver regenerates itself very easily because mature liver cells proliferate quite readily. The pancreas and liver also have a close developmental relationship, arising from the same tissue during embryonic development. This means that liver cells may be particularly suited to being turned into beta cells.

Researchers in Israel used a gene called PDX-1, which has long been known to play a role in pancreatic development and beta-cell function, to turn human liver cells from donated tissue into fully functioning, insulin-producing cells. Delivering PDX-1 to liver cells using a viral vector made the cells secrete insulin in much the same way as beta cells do: They expressed insulin, stored it in tiny compartments called granules, and secreted insulin in a glucose-dependent fashion. When the researchers transplanted these cells into diabetic, immune-deficient mice, they ameliorated high blood glucose for long periods of time. These findings were published in the May 31, 2005, issue of Proceedings of the National Academy of Sciences.

According to the researchers, the earliest application of this technology for treating Type 1 diabetes in humans might involve an autologous transplant (where the tissue to be transplanted comes from the person to receive it). The liver tissue could be taken via biopsy, converted into insulin-producing cells, then implanted back into the same person. This could overcome the shortage of donated tissue from cadaver donors and might even bypass the problem of autoimmunity.

In the future, another possible approach might be to deliver the genetic information directly to a person’s liver cells using a viral vector and converting liver cells into beta cells inside the person’s body (rather than removing liver cells, converting them, then reimplanting them). Whether this approach is doable, however, remains to be seen.

This column is written by Robert Dinsmoor, a Contributing Editor of Diabetes Self-Management.

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